Frontiers in Immunology (Apr 2021)

Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis

  • Mohamed El-Far,
  • Madeleine Durand,
  • Madeleine Durand,
  • Isabelle Turcotte,
  • Isabelle Turcotte,
  • Etienne Larouche-Anctil,
  • Mohamed Sylla,
  • Sarah Zaidan,
  • Sarah Zaidan,
  • Carl Chartrand-Lefebvre,
  • Carl Chartrand-Lefebvre,
  • Rémi Bunet,
  • Rémi Bunet,
  • Hardik Ramani,
  • Hardik Ramani,
  • Manel Sadouni,
  • Irina Boldeanu,
  • Annie Chamberland,
  • Sylvie Lesage,
  • Sylvie Lesage,
  • Jean-Guy Baril,
  • Benoit Trottier,
  • Réjean Thomas,
  • Emmanuel Gonzalez,
  • Emmanuel Gonzalez,
  • Ali Filali-Mouhim,
  • Jean-Philippe Goulet,
  • Jeffrey A. Martinson,
  • Seble Kassaye,
  • Roksana Karim,
  • Jorge R. Kizer,
  • Jorge R. Kizer,
  • Audrey L. French,
  • Stephen J. Gange,
  • Petronela Ancuta,
  • Petronela Ancuta,
  • Jean-Pierre Routy,
  • David B. Hanna,
  • Robert C. Kaplan,
  • Robert C. Kaplan,
  • Nicolas Chomont,
  • Nicolas Chomont,
  • Alan L. Landay,
  • Cécile L. Tremblay,
  • Cécile L. Tremblay

DOI
https://doi.org/10.3389/fimmu.2021.664371
Journal volume & issue
Vol. 12

Abstract

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Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH.

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